Project description:Whole transcriptome analysis performed on lung samples from dead covid-19 patients and healthy non-covid-19 individuals of multiple age groups.
Project description:COVID-19 continues to exact a toll on human health despite the availability of several vaccines. Bacillus Calmette Guérin (BCG) has been shown to confer heterologous immune protection against viral infections including COVID-19 and has been proposed as vaccine against SARS-CoV-2 (SCV2). Here we tested intravenous BCG vaccination against COVID-19 using the golden Syrian hamster model together with immune profiling and single cell RNA sequencing (scRNAseq). We observed that BCG vaccination conferred a modest reduction on lung SCV2 viral load, bronchopneumonia scores, and weight loss. This was accompanied by an increase in lung alveolar macrophages, a reversal of SCV2-mediated T cell lymphopenia, and reduced lung granulocytes. Single cell transcriptome profiling showed that BCG uniquely recruits immunoglobulin-producing plasma cells to the lung suggesting accelerated local antibody production. BCG vaccination also recruited elevated levels of Th1, Th17, Treg, CTLs, and Tmem cells, and differentially expressed gene (DEG) analysis showed a transcriptional shift away from exhaustion markers and towards antigen presentation and repair. Similarly, BCG enhanced lung recruitment of alveolar macrophages and reduced key interstitial macrophage subsets, with both cell-types also showing reduced IFN-associated gene expression. Our observations indicate that BCG vaccination protects against SCV2 immunopathology by promoting early lung immunoglobulin production and immunotolerizing transcriptional patterns among key myeloid and lymphoid populations.
Project description:In this dataset contains 3 cases of transcriptome information from 3 normal lung tissue, they respectively from lung squamous carcinoma tissue adjacent to carcinoma (C5), pneumonia lesions (C55) and lung bronchiectasis disease (C56), 6 cases from lung tissue samples of COVID - 19 patients (S528, S527, S59, S519, S52, S523).
Project description:To determine definitively whether lung myeloid cells exhibit a pro- or anti-inflammatory signature in COVID-19 disease, we performed digital spatial profiling using the nanoString GeoMx ImmuneOncology plus COVID-19 platform on CD68+ macrophages, myeloperoxidase+ granulocytes and cytokeratin+ epithelium in normal and COVID-19 lung tissue specimens, collecting RNA expression data for each type within 6-8 regions of 5mM tissue sections. One COVID-19 lung tissue yielded minimal sequence data and was excluded from analysis. A volcano plot and heat map of differentially expressed genes within macrophages demonstrate that COVID-19 lung macrophages when compared with normal lung macrophages exhibit a largely alternatively activated, wound-healing signature characterized by expression of the alternatively active macrophage marker CD163, complement/coagulation genes (C1QA, C1QB, THBS1, C1S, C1R), IL6 signaling (STAT2, STAT1) and wound healing (COL3A1, COL6A3), but also interferon response signatures (ISG15, OAS3, IFITM2, IFI6, HLA-A, HLA-B, HLA-C) (Fig. 3H-J). As one of the tissues used for macrophage spatial profiling was from a patient was positive for the virus at the time of death, we compared the expression profiles of virus+ and virus- specimens and found that macrophages in virus+ tissues predominantly expressed an interferon-associated signature
Project description:Genome-wide association studies (GWAS) have identified 19 risk variants associated with colorectal cancer. As most of these risk variants reside outside the coding regions of genes, we conducted cis-expression quantitative trait loci (cis-eQTL) analyses to investigate possible regulatory functions on the expression of neighboring genes. Forty microsatellite stable and CpG island methylator phenotype-negative colorectal tumors and paired adjacent-normal colon tissues were used for genome-wide SNP and gene expression profiling in our cis-eQTL analyses. This submission represents transcriptome component of study.
Project description:The outbreak of Coronavirus disease 2019 (COVID-19) throughout the world has caused millions of death, while the dynamics of host responses and the underlying regulation mechanisms during SARS-CoV-2 infection are not well depicted. Lung tissues from a mouse model sensitized to SARS-CoV-2 infection were serially collected at different time points for evaluation of transcriptome, proteome and phosphoproteome. We showed the ebb and flow of several host responses in the lung across viral infection. The signaling pathways and kinases regulating networks were alternated at different phases of infection. Our study not only revealed the dynamics of lung pathophysiology and their underlying molecular mechanisms during SARS-CoV-2 infection, but also highlighted some molecules and signaling pathways that might guide future investigations on COVID-19 therapies.
Project description:SARS-CoV-2 infects the respiratory tract, primarily causing pulmonary disease and cardiac complications described in many COVID-19 cases. To elucidate the molecular mechanisms of SARS-CoV-2 infection in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures, that were productively infected with SARS-CoV-2. SARS-CoV-2 variants of concern infected heart and lung cells with comparable efficiency. With CRISPR-Cas9 mediated knock-out of ACE2, we demonstrated that angiotensin converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types. Further processing of the spike protein in lung cells required TMPRSS2 while infection of cardiac cells was achieved through the endosomal pathway and Cathepsin L. Host responses were significantly different, with a strong interferon response following infection in cardiac cells but not in lung AT2 cells. Transcriptome profiling and phosphoproteomics demonstrated that response to SARS-CoV-2 depended strongly on the cell type. We evaluated antiviral drugs that are approved for treatment of COVID-19, drugs that showed antiviral activity in vitro but were not found to be effective in clinical trials or are still under investigation and drugs targeting molecules identified in our molecular datasets in both cell types. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational drug combinations for effective treatment of a virus that affects multiple organ systems.
Project description:Respiratory failure in COVID-19 is characterized by widespread disruption of the lung’s alveolar gas exchange interface. To elucidate determinants of alveolar lung damage, we performed epithelial and immune cell profiling in lungs from 24 COVID-19 autopsies and 43 uninfected organ donors ages 18-92 years. We found marked loss of type 2 alveolar epithelial (T2AE) cells and increased peri-alveolar lymphocyte cytotoxicity in all fatal COVID-19 cases, even at early stages before typical patterns of acute lung injury are histologically apparent. In lungs from uninfected organ donors, there is also progressive loss of T2AE with increasing age which may increase susceptibility to COVID-19 mediated lung damage in older individuals. In the fatal COVID-19 cases, macrophage infiltration differed according to the histopathological pattern of lung injury. In cases with acute lung injury, we found accumulation of CD4+ macrophages that express distinctly high levels of T-cell activation and co-stimulation genes and strongly correlate with increased extent of alveolar epithelial cell depletion and CD8 T-cell cytotoxicity. Together, our results show that T2AE deficiency may underlie age-related COVID-19 risk and initiate alveolar dysfunction shortly after infection; and we define immune cell mediators that may contribute to alveolar injury in distinct pathological stages of fatal COVID-19.